The objectives of this proposal are to evaluate the need for creatine and phosphocreatine in skeletal muscle by determining the consequences of specifically depleting muscle of these compounds and to answer the question: Do abnormalities of creatine metabolism cause disease of muscle? Depletion will be accomplished by feeding Beta-guanidinobutyric acid, or beta-guanidinopropionic acid. Both compounds inhibit creatine transport into muscle. Beta-guanidinopropionic acid is a poor substrate for creatine kinase and is phosphorylated in skeletal muscle to form a poor substitute for phosphocreatine. Beta-guanidinobutyric acid is not a substrate for creatine kinase. The ability of muscle to withstand phosphocreatine depletion will be evaluated in long-term studies and in studies of the responses to the superimposed stresses of thyrotoxicosis, vitamin E deficiency and hereditary muscular dystrophy. The function and metabolism of depleted muscle will be studied using intact muscles at rest, during contraction, and during recovery from contraction. Particular attention will be paid to the putative role of phosphocreatine in the control of glycolysis.